Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis

OBJECTIVE: To analyse the safety of leflunomide plus infliximab combination therapy, in adult rheumatoid arthritis (RA) patients. PATIENTS: A retrospective study of 17 adult patients with active RA (DAS 28 = 5.94 +/- 0.88 at baseline) who were treated with a combination of leflunomide plus infliximab after failure of treatment with other DMARDs. 13 patients were treated for a minimum of 3 months with leflunomide without toxicity before beginning infliximab. Treatment was begun simultaneously with both drugs in 4 patients. Side effects (clinical and biological) and efficacy (DAS 28) were evaluated at each infliximab infusion (3 mg/kg at week 0, 2, 6 and then every 8 weeks). RESULTS: Thirteen patients experienced 20 types of side effects and 8 of them stopped the combination therapy. The causes of discontinuation were congestive heart failure (1 case), hypertension with thoracic pain (2 cases), eczematous skin patches (2 cases) and neutropenia (3 cases). No death was registered. Nine RA patients continuted the therapy with a median follow-up of 22 weeks. Only 4 of them experienced no side effects. Eight patients were positive for antinuclear antibodies (ANA) and 1 for double-stranded DNA (dsDNA) antibodies at study entry. After treatment, 13 and 5 patients tested positive respectively for ANAs and dsDNA antibodies. There was no relationship between discontinuation and ANA/dsDNA positivity. CONCLUSION: In this cohort, adverse events were not very different from those seen in patients on either treatment alone and the combination of leflunomide plus infliximab did not appear to be as badly tolerated as described in a previous study.     

Histological changes in bone marrow after treatment of infliximab for rheumatoid arthritis

To investigate histological evidence of bone remodeling in response to infliximab for rheumatoid arthritis (RA), bone marrow tissues were extracted from ten RA patients at the time of total knee arthroplasty after treatment of infliximab for an average of 16 months (range, 8–24 months). The patients had a mean age of 65.3 years (range, 57–76 years) with 4.8 mg/week of methotrexate (MTX; 4–6 mg) and 3.8 mg/day of prednisolone (2–5 mg). Control samples were obtained from ten RA patients who did not undergo infliximab therapy. These patients had an average age of 67.6 years (range, 59–78 years) and received 5.2 mg/week of MTX (4–6 mg) and 4.0 mg/day of prednisolone (2–5 mg). Histological examination of structural differences between the infliximab and control groups in bone marrow was performed using hematoxylin and eosin (H & E) to evaluate differences. In immunohistochemical examination, the expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), receptor activator of nuclear (kappa) B ligand (RANKL), osteoprotegerin (OPG), and osteopontin (OPN) were compared between both groups. H & E staining revealed that the bone marrow tissues of the RA patients who underwent infliximab therapy demonstrated newly formed thickness of interstitial septum among the trabeculae as compared with the control group. Moreover, immunohistochemical examinations revealed that TNF-α, IL-6, RANKL, OPG, and OPN were expressed in this newly formed bone after infliximab therapy. Therefore, treatment with infliximab improved the histological changes with respect to bone metabolism in the newly formed bone marrow tissues.     

Haemophagocytic syndrome in a rheumatoid arthritis patient treated with infliximab

SIR, Inhibitors of tumour necrosis factor (TNF-; monoclonalantibodies or soluble receptors) have proven their efficacyin the treatment of rheumatoid arthritis (RA) and are currentlyunder investigation in other chronic inflammatory diseases.However, an increase in infectious complications is noticedwith these molecules. We report an RA patient who developedhaemophagocytic syndrome (HPS) while she was being treated withinfliximab. A 46-yr-old woman had suffered from seropositive RA (AmericanRheumatism Association criteria) since 1999. Despite activetreatment with steroids, methotrexate and sulphasalazine, thedisease remained active [disease activity score (DAS) >4.5].Treatment with infliximab (3 mg/kg) was started in December2000 with a good     

Pregnancy in a rheumatoid arthritis patient on infliximab and methotrexate

SIR, A lady was diagnosed with rheumatoid arthritis at the ageof 29. She was initially treated with sulphasalazine (3 g/day)and then azathioprine (eventually 250 mg/day) was added. Thisfailed to control her disease, so hydroxychloroquine (400 mg/day)was added. On this combination of drugs (with 5 mg prednisoloneand diclofenac 150 mg/day) her disease appeared to be comingunder control. At this point the patient decided she would like to try fora baby. The hydroxychloroquine and sulphasalazine were stoppedand the prednisolone was     

Pulmonary hypertension in a patient with rheumatoid arthritis treated with leflunomide

SIR, Leflunomide (LFN) is a disease-modifying anti-rheumaticdrug that reduces the signs and symptoms of rheumatoid arthritis(RA) and delays the radiological progression of the disease[1, 2]. The most common adverse reactions leading to LFN withdrawalare gastrointestinal symptoms, skin reactions, alopecia, systemicarterial hypertension and elevated liver enzymes. Although asmall percentage of patients with RA develop systemic arterialhypertension while taking LFN, no other serious cardiovascularadverse reactions have been reported [3]. Here we report one patient with severe refractory     

Safety and efficacy of leflunomide and infliximab versus methotrexate and infliximab combination therapy in rheumatoid arthritis

SIR, There is little experience about the safety and efficacyof the combination of leflunomide with infliximab (LEF-INF)in rheumatoid arthritis (RA), and published data have shownsome controversy [1–4]. We have read with interest thepaper of Flendrie et al. [5], where they compare previous andconcomitant LEF therapy plus INF with treatment with INF plusother DMARDs [5]. In order to provide further information inthis field we present our results on the safety     

The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis

OBJECTIVE: To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis. METHODS: In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF. RESULTS: Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer. CONCLUSIONS: The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.     

Diffuse alveolar hemorrhage after leflunomide therapy in a patient with rheumatoid arthritis

We report the case of a young man, affected by rheumatoid arthritis who developed a rapid-onset short-of-breath, hemoptysis, and severe weakness, about 2 weeks after the administration of leflunomide. Chest radiography showed central bilateral opacities and pleural effusion as confirmed by the high-resolution computed tomography that demonstrated diffuse ground-glass and interlobular septal thickening as well. On admission at the Emergency Department, a microhematuria and a severe anemia were also documented. On the basis of the clinico-radiologic presentation, a pulmonary hemorrhage was likely to occur; so to clarify the origin of this process, a complete serologic examination was performed but all the antibodies were negative. Finally a renal biopsy was performed and it showed a pauci-immunologic glomerulonephritis and the bronchioloalveolar lavage confirmed the diffuse alveolar hemorrhage. In conclusion, the diagnosis of leflunomide-pulmonary-renal syndrome was rendered. The treatment with leflunomide was suspended; the conditions of the patient gradually improved and he became completely asymptomatic 1 week later.     

Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with infliximab

Anti-TNFalpha strategies can result in significant clinical benefits in rheumatoid arthritis (RA), but with an increased rate of opportunistic infections. Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised hosts, principally in HIV patients. VL in RA patients treated with TNFalpha antagonists is an extremely rare event, and only one case has been described. Here we report a case of VL, occurring after 9 infusions of infliximab in association with azathioprine, in a patient who developed blood cytopenia, fluctuant fever, and splenomegaly.     

Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept

OBJECTIVE: The role of alternative tumor necrosis factor (TNF) antagonist therapies in the context of failure of initial TNF antagonist therapy in patients with rheumatoid arthritis (RA) has yet to be clearly defined. The goal of this study was to determine the efficacy of etanercept in patients who failed to respond to infliximab. METHODS: Ninety-five patients with RA who failed to respond to infliximab and methotrexate were treated with etanercept (with continuation of concomitant methotrexate). Thirty-four patients never achieved a response to infliximab (primary nonresponse), 38 had an initial response to infliximab but relapsed (secondary nonresponse), and 23 demonstrated toxicity. Disease Activity Score in 28 joints (DAS28), European League Against Rheumatism (EULAR) response, and American College of Rheumatology (ACR) response were determined after 12 weeks of etanercept. RESULTS: After 12 weeks of etanercept, 38% of patients achieved an ACR 20% response (ACR20) on etanercept. Of these, 24% and 15% achieved ACR50 and ACR70 responses, respectively. In the primary infliximab nonresponse group, 42%, 30%, and 15% achieved ACR20, ACR50, and ACR70 responses, respectively; the percentages for the secondary nonresponse group were 34%, 21%, and 14%, respectively. Significant DAS28 reductions were observed in the entire cohort and nonresponse subtype groups. Sixty-one percent of the cohort achieved either a moderate or good EULAR score (67% of primary and 56% of secondary infliximab failures). No toxicity was observed in patients who stopped infliximab due to intolerance; 19 of 23 continued etanercept after week 12. CONCLUSION: This study confirms that etanercept is effective in patients who fail to respond to infliximab and suggests a higher response in patients who have never had a response to infliximab.     

Clinical outcome in patients with rheumatoid arthritis switched to tocilizumab after etanercept or infliximab failure

The present study retrospectively assessed the efficacy of tocilizumab in patients with rheumatoid arthritis (RA) who failed to respond to treatment with etanercept or infliximab. A retrospective study of 33 RA patients who did not respond to etanercept or infliximab was conducted. Responses of subjects switching from etanercept to tocilizumab (n?=?17) were compared with those switching from infliximab to tocilizumab (n?=?16). Treatment with disease-modifying antirheumatic drugs before the switch, especially methotrexate (MTX), was maintained. Disease activity was assessed by the Disease Activity Score 28-C Reactive Protein (DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Patients who switched from etanercept were significantly less likely to have used MTX and were significantly older than patients who switched from infliximab. In both groups, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values at 24 weeks with no significant differences between groups. However, at week 52, DAS28-CRP, SDAI, and CDAI values in the group switched from etanercept were significantly worse than those in the group switched from infliximab. All patients switched from infliximab were using MTX. In the evaluation between patients who switched from etanercept monotherapy, etanercept plus MTX, and infliximab plus MTX, a significant improvement from baseline was seen in DAS28-CRP, SDAI, and CDAI for all patients at 24 weeks with no significant differences between groups. Disease activity was maintained at 52 weeks in the group that switched from etanercept plus MTX and infliximab plus MTX. However, the efficacy of tocilizumab was decreased in the group that switched from etanercept monotherapy. Switching from etanercept plus MTX or from infliximab plus MTX to tocilizumab plus MTX improved response to therapy, but switching from etanercept monotherapy to tocilizumab monotherapy did not improve response to therapy.